To examine whether sleep disordered breathing (SDB), Apolipoprotein 54 (APOE 54) status, increasing age and their interactions will predict rate of cognitive decline in veterans who have PTSD, a population already at risk for cognitive deficits. Specific Aims: To address the question of how SDB and APOE status affect cognitive decline in a sample of PTSD patients, specific hypotheses that tease apart the effects of APOE status and SDB on cognitive decline will be tested. Hypothesis 1: In individuals with PTSD, three risk factors (sleep disordered breathing, APOE 54 genotype, age) and their interactions will predict rate of decline in performance on measures of cognition. Hypothesis 2: APOE 54 moderates the effect of sleep disordered breathing on cognitive decline. Hypothesis 3: Sleep disordered breathing will mediate any negative impact of APOE 54 on cognitive decline. Relevance to Veterans'Health/VA Mission: A number of veterans suffer from PTSD during their post-war life. As PTSD veterans age, they are at higher risk for cognitive decline and dementia. Most Vietnam veterans are male and as many as 29% of adult males have some degree of SDB (Young et al., 1993). Emerging evidence based on recent findings indicate that posttraumatic sleep disturbance frequently manifests with a combination of insomnia and a higher-than-expected prevalence of SDB (Lamarche &De Koninch, 2007;Krakow et al., 2002). The proposed research will determine to what degree veterans with PTSD are at accelerated risk for cognitive decline if they are APOE 54 carriers and/or have SDB. Careful assessment of these risk factors for development of cognitive impairment or dementia in this population is especially timely since there are established treatments for SDB and there are major NIH initiatives on the diagnosis and treatment of MCI in the general population. After completing our study we will be in a position to estimate the potential effect of treatments for SDB, as well as characterize our veteran population to best estimate response to treatment. Such information could lead to a firm basis for proposing randomized clinical trials in the veteran PTSD population at similar risk for developing cognitive impairment. Now is the time to undertake such work, while vulnerable Vietnam-era veterans are still just at risk, before developing dementia. Such efforts might help mitigate unnecessary personal suffering in veterans and their families and reduce future demands on the VA health care system. Design/Analysis: A longitudinal design will be employed using a random regression model. Setting: The study will be conducted at the VA Palo Alto Health Care System. Participants: Our hypotheses will be tested longitudinally in 90 PTSD and 90 non-PTSD patients, 55 years or older. Measurements: The primary outcome measure, Rey Auditory Verbal Learning Test, other cognitive measures, and SDB will be assessed at baseline and annually. APOE status will be collected at baseline only. PUBLIC HEALTH RELEVANCE: A significant number of veterans either suffer from PTSD currently or have suffered from PTSD at some time during their post-war life. We argue that as the population of veterans with PTSD ages, they are at higher risk for cognitive decline and dementia. We emphasize that most veterans are male and that as many as 29% of adult males have some degree of SDB (Young et al., 1993). Furthermore, emerging evidence indicate that posttraumatic sleep disturbance frequently manifests with a combination of insomnia and a higher-than- expected prevalence of SDB (Lamarche &De Koninch, 2007;Krakow et al., 2002). The proposed research will determine to what degree this population of veterans with PTSD is at accelerated risk for cognitive decline if they are APOE 54 carriers and/or if they have SDB. On completion of the study, we will be in a position not only to estimate the potential effect of treatments for SDB, but also to be able to characterize our veteran population and estimate the likelihood of their responding to treatment.